ABSTRACT Over the past 15 years, the US has been affected by increasing prescription and illicit opiate/opioid abuse, addiction, and overdose. Research into the enhancement of treatment options for individuals with opiate/opioid use disorder (iOUD) is clearly a priority. The development of neuroscience-informed behavioral therapies that could be used as adjuncts to improve effectiveness of medication-assisted interventions in iOUD is a national priority, a response to the opiate crisis. The 8-week Mindfulness-Oriented Recovery Enhancement (MORE) decreases opioid misuse, craving, and cue-reactivity, and enhances natural reward responsiveness, effects attributed to restructuring of hedonic dysregulation, in opioid misusing patients. Improved function and increased gray matter in relevant brain regions [e.g., the prefrontal cortex (PFC)] have been shown with other 8-week mindfulness interventions in non- addicted individuals. However, the neural mechanisms underlying MORE-related changes in iOUD are unknown. The Impaired Response Inhibition and Salience Attribution (iRISA) model highlights the importance of mesocorticostriatal regions, including the PFC, to enhanced salience of drugs relative to natural rewards concomitant with decreased inhibitory control, core substrates underlying drug addiction. Given these commonalities, we propose to study the neural correlates of iRISA as contributing to and predictive of the impact of MORE on addiction outcome in iOUD. Using a pre-post randomized treatment design with a 3-months follow-up, we will examine the impact of MORE [vs. treatment-as-usual (TAU), as add-ons to methadone maintenance] on neural functional and structural plasticity, and clinical outcomes (including daily ecological momentary assessments), in treatment-seeking iOUD (with primary use of heroin). Treatment-seeking iOUD will be randomized to 8-weeks of MORE or psychosocial TAU and scanned with magnetic resonance imaging immediately before and after treatment. Healthy controls will be scanned at similar time intervals. We hypothesize that compared with the controls, TAU or pre-MORE, post-MORE subjects will show normalizations or changes in: a) frontostriatal function during reward processing (i.e., enhanced natural reward and reduced drug cue processing) and inhibitory control; b) meso- corticostriatal resting-state functional connectivity; and c) gray matter in regions associated with reward processing and inhibitory control. Clinical outcome will be assessed during, immediately and 3-months after MORE or TAU. We hypothesize that brain changes post-MORE>pre-MORE or TAU will predict clinical improvement (treatment retention, abstinence, amount/frequency of opiate use and craving) such that the more the neural change, the better the outcomes (healthy controls provide direction of results). In whole-brain analyses we consider the possibility that recovery entails effects in other networks that compensate for deficits. Results will help identify individual variability in the brain regions/circuits that support reward processing, including cue reactivity, and inhibitory control and that could change with, and predict, response to MORE, ultimately contributing to precision medicine in OUD.